Under these conditions, a constant amount of drug is eliminated per unit time no matter how much drug is in the body. At high drug concentrations, the maximal rate of metabolism is reached and cannot be exceeded. In this situation, CL int decreases as unbound drug concentration increases (see equation 5) and steady state drug concentration increases more than proportionately with dose (equation 3). In some cases, unbound drug concentration is close to or above K m at therapeutic doses, and the kinetics begin to become non-linear (seeįig. Usually, unbound plasma drug concentration (C u) in the therapeutic range is very small compared to the K m for the metabolising enzyme and equation 5 approximates toĬL int is then independent of unbound drug concentration which is therefore linear with dose. Where V max is the maximum rate of metabolism at high concentrations of unbound drug and K m is the unbound drug concentration at half V max. Equation 4 can then be rearranged to give a function for intrinsic clearance (see also equation 1). In pharmacokinetic terms, v is equivalent to the rate of elimination (v = C u x CL) and S is equivalent to the unbound drug concentration (C u). Km is a measure of the affinity of the substrate for the enzyme. Where v is the velocity of reaction, S is the substrate concentration, V max is the maximum velocity at very high substrate concentrations and K m is the substrate concentration at half V max. The dependence of the rate of an enzyme reaction on substrate concentration is given by the Michaelis-Menten equation and is illustrated in Fig. The metabolism of drugs is carried out by a variety of enzymes such as cytochrome P450 and N-acetyltransferase.
Saturation of elimination mechanisms causes a change in intrinsic clearance However, there are some situations where this predictable relationship between dose rate and C ss breaks down due to dose dependency of F, f u and/or CL int.ġ. Where f u is the fraction unbound to protein.Ĭombining equations 1 and 2, the determinants of C ss during chronic dosing areį, f u and CL int usually do not change with drug concentration so that C ss is directly proportional to dose rate. In most dosing situations, total clearance (CL) is determined by protein binding and intrinsic clearance (CL int) (Article 4 - `How drugs are cleared by the liver' Aust Prescr 1990 13:88-9). In a previous article (Article 1 - `Clearance' Aust Prescr 1988 11:12-3), it was shown that the steady state blood concentration (C ss) is a function of both the dose and the clearance of the drug. What causes non-linear pharmacokinetic behaviour? This is known as non-linear pharmacokinetic behaviour and can cause problems when adjusting doses. However, for some drugs, the plasma drug concentration changes either more or less than would be expected from a change in dose rate. if the dose rate is increased or decreased say two-fold, the plasma drug concentration will also increase or decrease two-fold.
When the dose of a drug is increased, we expect that the concentration at steady state will increase proportionately, i.e. What is meant by non-linear pharmacokinetics?
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